Borrelia crocidurae meningoencephalitis, West Africa.
Persons included in our study had clinical signs and symptoms of meningitis or encephalitis, or both, and were selected from the 11 patients with cases of B. crocidurae TBRF that were reported to and confirmed by the National Reference Center for Borrelia (NRCB) in France during 2009-2011. The NRCB is the reference laboratory responsible for the epidemiologic surveillance of TBRF in France. Clinical meningitis or encephalitis was defined as previously reported (2). Borrelia species were detected in Giemsa-stained thin blood smears by microscopy and quantitative buffy coat analysis (Becton Dickinson, Le Pont de Claix, France) when available (4). Borrelia spp. were detected and identified by using 16SrRNA PCR and subsequent sequencing as described (8). We tested serum and CSF samples with standardized antibody assays for detection of Borrelia spp. that cause Lyme disease (Table).
Among the 11 TBRF cases reported to NRCB during the 3-year study, we identified 4 (36%) cases of clinical meningitis or encephalitis, or both. The epidemiologic, clinical, and laboratory findings and the treatment of the 4 patients are documented in the Table. Three of the 4 patients were adult men, 26-57 years of age, and 1 was a 7-year-old girl. None of the patients were immunocompromised. They were all given appropriate antimalarial chemoprophylaxis. Patients 1 and 4 experienced their first febrile episode in Africa and were empirically treated with antimalarial drugs without biological confirmation of Plasmodium infection.
At the time of admission to health care facilities, all patients had fever and headache. Patients 2, 3, and 4 had signs of meningitis, including neck stiffness; patients 2 and 4 also had phonophobia and photophobia. Patients 1 and 4 had encephalitis with drowsiness, which for patient 4 was accompanied by cerebellar syndrome (dysarthria and dysmetria). All patients except patient 3 underwent computed tomography scanning of the brain; no abnormality was detected. The 2 patients with encephalitis were examined by magnetic resonance imaging; in patient 4, a predominant positive contrast of the cerebellum leptomeninges on the right side was observed.
For all patients, 16S rRNA PCR and sequencing identified B. crocidurae (8) in blood samples. Laboratory analysis of the 4 CSF samples showed a lymphocytic pleocytosis, high protein concentrations, and a glucose value within reference range (Table). The molecular methods applied to CSF samples confirmed neurologic B. crocidurae infection in patients 1, 2, and 3. Serum samples collected from patients 1 and 4 at the time of diagnosis were tested by using Lyme disease serodiagnostic assays. ELISA detected substantial levels of IgM and IgG in samples from both patients; 1 was confirmed by Western blot analysis. The CSF sample from patient 4 showed a low level of IgG (Table).
All cases were treated with doxycycline or ceftriaxone, or both (Table). In all patients, fever resolved within 3 days of the beginning of the appropriate treatment, and the outcomes were favorable. No Jarisch-Herxheimer reaction was observed.
B. crocidurae-associated TBRF is an emerging disease that is considered to be benign (1,9). However, the series of infections reported here suggest that severe neurologic complications, notably, meningitis and encephalitis, occur more frequently than previously thought and could be particularly common in travelers who acquired this infection in West Africa. For the patients we studied, the earliest neurologic signs occurred during the second febrile episode, confirming previous studies reporting the onset of neurologic complications after the first episode (2). However, facial palsy, often considered to be among the main clinical signs and symptoms of neuroborreliosis caused by TBRF-associated Borrelia species, was not observed in these patients (2). A similar clinical manifestation described in a recent case report of B. crocidurae encephalitis is entirely consistent with our observations (3).
Functional and experimental studies have focused on the capacity of TBRF-associated Borrelia species to cross the blood-brain barrier and to persist in the brain (2-7,10,11). These studies have established B. crocidurae as the most neurotropic species, an observation consistent with this and other case series and case reports. In animal models, this feature has been associated with the presence of vascular microemboli in the brain of infected animals and the particular ability of B. crocidurae to form and bind to erythrocyte rosettes, a phenomenon also involved in cerebral malaria pathogenesis. Erythrocyte aggregation might prevent host-pathogen interactions and thereby protect the spirochetes from the specific immune response (10,12,13).
The rather high frequency and severity of neurologic complications associated with B. crocidurae infection raise the problem of distinguishing it from cerebral malaria, because the areas of endemicity of these 2 diseases largely coincide (1,9). Indeed, relapsing fever is frequently misdiagnosed as malaria, as it was for 2 of the patients we studied, who were initially treated with antimalarial drugs (14). In this context, quantitative buffy coat analysis that can effectively detect each pathogen in blood might be of particular interest (4). In addition, our study confirms the usefulness of molecular methods applied to blood and CSF samples to confirm Borrelia infection (3,8). The negative result obtained by PCR of CSF from patient 4 could have been the consequence of inappropriate storage of the sample at high room temperature for 72 hours before analysis.
Lyme disease serodiagnostic testing of serum and CSF samples might be helpful. Indeed, cross-reacting IgG and IgM were detected by ELISAs and in Western blot assays. Because Lyme disease is endemic to France, our results could have been caused by the actual detection of B. burgdorferi sensu lato antibodies, although none of the patients had a known history of Lyme disease.
No specific recommendations have been proposed for the treatment of patients with TBRF neuroborreliosis. Erythromycin and penicillin have been reported to be ineffective (5,6). In our series, all patients were prescribed either ceftriaxone or doxycycline, or both (Table), resulting in successful treatment of the disease. Thus, from the literature and our own experience, we suggest that TBRF with neurologic involvement should be treated with ceftriaxone or doxycycline for at least 21 days.
Our study highlights the frequent occurrence of meningitis or encephalitis in patients with B. crocidurae TBRF acquired in West Africa. The clinical and radiologic manifestations suggest that this infection could be more severe than previously thought. Consequently, travelers returning from West Africa with febrile neurologic disorders should be tested immediately for biological confirmation of Borrelia infection through blood and CSF analyses, including molecular methods.
We thank Laurence Courdavault, Patrick Plesiat, Ian Dorval, Jacques Croize, and the technicians of the biology laboratory of the Centre Hospitalier d'Argenteuil for their help with diagnostic confirmation and for providing samples from the patients. We also thank Olivier Epaulard for his insightful comments on the manuscript.
Dr Goutier is an infectious disease specialist at the Groupe Hospitalier Mutualiste in Grenoble, France. Her research interests include clinical infectious diseases, antimicrobial drugs resistance, and epidemiology of nosocomial pathogens.
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Sandrine Goutier,  Elisabeth Ferquel,  Claudine Pinel, Annick Bosseray, Bruno Hoen, Gerard Couetdic, Amina Bourahoui, Claire Lapostolle, Herve Pelloux, Martine Garnier, Natacha Sertour, Isabelle Pelloux, Patricia Pavese, and Muriel Cornet
 These authors contributed equally to this work.
Author affiliations: Grenoble Teaching Hospital, Grenoble, France (S. Goutier, C. Pinel, A. Bosseray, H. Pelloux, I. Pelloux, P. Pavese, M. Cornet); Pasteur Institute, Paris, France (E. Ferquel, M. Garnier, N. Sertour), Joseph Fourier University, Grenoble (C. Pinel, H. Pelloux, M. Cornet); Besancon Teaching Hospital, Besancon, France (B. Hoen, G. Couetdic); Argenteuil Hospital, Argenteuil, France (A. Bourahoui); and Laennec Hospital, Quimper, France (C. Lapostolle)
Address for correspondence: Sandrine Goutier, Service de Medecine Interne, Groupe Hospitalier Mutualiste de Grenoble, 8 Rue du Docteur Calmette, 38028 Grenoble Cedex 1, France; email: sandrinegoutier@ hotmail.com
Table. Epidemiologic, clinical, and laboratory findings and treatment for patients with Borrelia crocidurae meningoencephalitis * Variables Patient 1 Patient 2 Demographic factor Age, y/sex 36/M 57/M Country of origin/of Senegal/France France/France residence Travel country Senegal Senegal Travel dates 2009 Mar-May 2010 May Travel duration, d 53 15 Travel accommodation Family house Hotel Arthropod or insect bite No Yes report Individual vector No No First suspected diagnosis Malaria/quinine Sinusitis ([dagger])/ presumptive treatment Symptoms Oral temperature Yes Yes >38.5[degrees]C Chills No No Total no. febrile 2/1 4/2 episodes/no. before diagnosis Length of acute febrile 2-8 2-6 episodes, d Afebrile periods between 15 2-15 febrile episodes, d Asthenia/anorexia/weight Yes/no/no Yes/yes/yest loss Headache Yes (severe) Yes Myalgia No No Photophobia, phonophobia No Yes Neck stiffness No Yes Cerebellar syndrome No No Drowsiness Yes No Imaging results Brain CT scan Normal Normal Brain MRI Normal ND Serologic results Leukocytes, g/L 4.7 15.8 Hemoglobin, g/L 134 139 Platelets, g/L 245 273 C-reactive protein, mg/L 103 4 Creatinine, [micro]mol/L 107 76 Borrelia spp. detection, +([section]) y+([paragraph]) Giemsa-stained blood smear Quantitative buffy coat ND ND ELISA anti-B. burgdorferi (titer) Siemens Enzygnost Lyme +(11.3) ND link VlsE/IgG (#) Siemens Enzygnost +(3.7) ND Borreliosis/IgM (#) Western blot anti-B. burgdorferi Bio-Advance IgG anti +/-/-/+ ND -VlsE/p41/p83/p21 (#) EUROIMMUN IgG anti-p17/ ND ND p19/p21/p25/p30/p31/ p39/p83/VlsE (#) Meridian Bioscience IgM ND ND garinii/afzelii/p41/ p39/p17 (#) Bio-Advance IgM +/+ ND anti-p25/p83 (#) 16S rRNA PCR Borrelia/ +/B. crocidurae +/B. crocidurae identification CSF test results Leukocytes, 405 217 cells/[mm.sup.3] % Lymphocytes 94 80 Erythrocytes, 0 7 cells/[mm.sup.3] Protein, g/L 0.66 1.38 Glucose, mmol/L 3.1 2.7 Chloride, mmol/L 114 113 Lactate, mmol/L ND ND Direct examination - - (Gram stain) Conventional bacterial - - culture 16S rRNA PCR Borrelia/ +/B. crocidurae +/B. crocidurae identification ELISA anti -B. burgdorferi Siemens Enzygnost Lyme ND ND link VlsE/IgG (#) Siemens Enzygnost ND ND Borreliosis/IgM (#) Treatment Ceftriaxone Doxycycline (daily dose/total d) (2 g/21) (100 mg 2xd/10) Variables Patient 3 Patient 4 Demographic factor Age, y/sex 7/F 26/M Country of origin/of France/France Senegal/France residence Travel country Senegal Senegal Travel dates 2011 Feb-May 2011 Aug-Sep Travel duration, d 15 35 Travel accommodation Hotel Family house Arthropod or insect bite No No report Individual vector No No First suspected diagnosis Gastroenteritis Malaria/piperaquin ([dagger])/presumptive treatment Symptoms Oral temperature Yes Yes >38.5[degrees]C Chills Yes Yes Total no. febrile 6/5 2/1 episodes/no. before diagnosis Length of acute febrile 2 2-6 episodes, d Afebrile periods between 2-13 34 febrile episodes, d Asthenia/anorexia/weight Yes/no/no Yes/no/no loss Headache Yes (severe) Yes (severe) Myalgia No Yes Photophobia, phonophobia No Yes Neck stiffness Yes Yes Cerebellar syndrome No Yes Drowsiness No Yes Imaging results Brain CT scan ND Normal Brain MRI ND Abnormal Serologic results Leukocytes, g/L 13.0 8.4 Hemoglobin, g/L 115 131 Platelets, g/L 295 103 C-reactive protein, mg/L 57 150 Creatinine, [micro]mol/L 42 99 Borrelia spp. detection, +([section]) + ([paragraph]) Giemsa-stained blood smear Quantitative buffy coat ND + ELISA anti-B. burgdorferi (titer) Siemens Enzygnost Lyme ND +(19) link VlsE/IgG (#) Siemens Enzygnost ND +(1.21) Borreliosis/IgM (#) Western blot anti-B. burgdorferi Bio-Advance IgG anti ND ND -VlsE/p41/p83/p21 (#) EUROIMMUN IgG anti-p17/ ND -/-/-/-/-/-/-/**/** p19/p21/p25/p30/p31/ p39/p83/VlsE (#) Meridian Bioscience IgM ND ND garinii/afzelii/p41/ p39/p17 (#) Bio-Advance IgM ND ND anti-p25/p83 (#) 16S rRNA PCR Borrelia/ +/B. crocidurae +/B. crocidurae identification CSF test results Leukocytes, 258 156 cells/[mm.sup.3] % Lymphocytes 90 84 Erythrocytes, 12 5 cells/[mm.sup.3] Protein, g/L 0.39 0.44 Glucose, mmol/L 2.69 2.9 Chloride, mmol/L 117 115 Lactate, mmol/L 1.5 2.2 Direct examination - - (Gram stain) Conventional bacterial - - culture 16S rRNA PCR Borrelia/ +/B. crocidurae - identification ELISA anti -B. burgdorferi Siemens Enzygnost Lyme ND - ([double dagger]) link VlsE/IgG (#) Siemens Enzygnost ND - Borreliosis/IgM (#) Treatment Ceftriaxone (2 Doxycycline (daily dose/total d) g/14) (100 m 2x d/21), ceftriaxon (2 g/15) * CT, computed tomography; MRI, magnetic resonance imaging; ND, not done; +, positive; -, negative; CSF, cerebrospinal fluid. ([dagger]) First suspected diagnosis was not biologically confirmed. ([double dagger]) 7 kg in 3 wk. ([section]) Second sample was positive. ([paragraph]) First sample was positive after review prompted by the quantitative buffy coat result. (#) Siemens, Erlangen, Germany; Bio-Advance, Bussy Saint Martin, France; EUROIMMUN Medizinische Labordiagnostika AG, Lubeck, Germany; Meridian Bioscience, Paris, France. ** Ambiguous. ([dagger][dagger]) At 12-fold dilution (low level).
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|Author:||Goutier, Sandrine; Ferquel, Elisabeth; Pinel, Claudine; Bosseray, Annick; Hoen, Bruno; Couetdic, Ger|
|Publication:||Emerging Infectious Diseases|
|Article Type:||Disease/Disorder overview|
|Date:||Feb 1, 2013|
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